tbuckley/cabot-search huggingface dataset:
PB2244: THE VALUE OF ANEMIA FOR ORGAN DAMAGE EVALUATION IN SYSTEMIC SCLEROSIS PATIENTS:A MULTI-CENTER RETROSPECTIVE STUDY
Authors: Z. Li, D. Xu, T. Li, R. Mu
Journal: HemaSphere (2022)

Background: Systemic sclerosis (SSc) is a systemic autoimmune disease with multiple organ damage. Scleroderma Clinical Trials Consortium (SCTC) has developed the Damage Index (DI) in SSc to quantify organ damage in SSc. While the relationship between the SCTC-DI and basic clinical and laboratory features remains unclear. Aims: To describe the SCTC-DI in SSc patients from Peking University Third Hospital SSc cohort (PKUTH-SSc) and Peking University People’s Hospital SSc cohort (PKUPH-SSc). And to develop models to discriminate higher risk of organ damage and predict new-onset organ manifestation within 5 years. Methods: Patients were recruited from PKUTH-SSc and PKUPH-SSc cohort between January 2001 to July 2021. All clinical and laboratory results were identified at initial visit and at follow-up timepoint. And extracted from electronic medical records. SCTC-DI was calculated as previously reported. LASSO algorithm was performed to select and sort the statistically significant clinical features. Logistic regression and Cox survival analysis were used for developing the evaluation model of SCTC-DI risk and prediction model for new-onset organ damage respectively. Results: A total of 155 and 278 SSc patients fulfilled selection criteria were enrolled in our study from PKUTH-SSc and PKUPH-SSc cohort respectively. Using LASSO-Logistic regression, we developed a model included underweight, age, duration since first symptom onset, steroids usage at baseline, positive anti-RNP/Sm autoantibody, ESR level and anemia at baseline to assess the high-risk SCTC-DI score. ROC analysis revealed a good discriminatory capability of the SCTC-DI risk group with ROC area under the curve of 0.75 (95% CI 0.70 to 0.79) using this model. Furthermore, in our follow-up study, anemia at baseline was independently related to 5-year organ damage progression (HR=1.67, 95% CI 1.11 to 2.53, p=0.014). As for the typical organ damage profile, patients with anemia at baseline were more likely to develop musculoskeletal and skin (60.6% vs 39.5%, p<0.001), gastrointestinal (62.3% vs 44.6%, p<0.001), cardiovascular (16.6% vs 10.1%, p=0.046) and renal (3.4% vs 0.0%, p=0.004) system damage compared to patients without anemia. While during follow-up, progression of the cardiovascular system damage was more common in anemia patients (14.5% vs 5.6%, p=0.031). Summary/Conclusion: This study based on the PKUTH-SSc and PKUPH-SSc cohort is the first retrospective study describe the SCTC-DI of SSc patients in external cohorts. Our results highlight the value of anemia at initial visit in discriminating high SCTC-DI score and predicting 5-year organ damage progression, demonstrating the regular and careful monitoring of these patients may help to improve the prognosis of organ damage in SSc.
PB2172: IRON OXIDE NANOPARTICLES INHIBIT DIFFUSE LARGE B LYMPHOMA CELL SURVIVAL AND INVASION
Authors: L. Yan-Li, H. Qi-Tang, H. Quan-Quan, W. Zhao-Feng
Journal: HemaSphere (2022)

Background: Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma world wide. It is a phenotypically and genetically heterogeneous disease, accounting for 30-40% of all cases. 50%-70% of patients can be cured by the R-CHOP regimen, but nearly one-third of patients develop relapsed or refractory disease. Until now, the Food and Drug Administration (FDA)-approved iron supplement ferumoxytol and other iron oxide nanoparticles have been used for treating iron deficiency, as contrast agents for magnetic resonance imaging and as drug carriers. But recently, more studies have revealed a hidden intrinsic therapeutic effect of ferumoxytol on tumors, but the role and mechanism in DLBCL has not been reported yet. Aims: The purpose of this study is to investigate the effect of iron oxide nanoparticles on DLBCL cells proliferation and migration by in vitro and in vivo. Methods: Different concentrations of iron oxide nanoparticles were applied to DLBCL cell lines, such as SUDHL-2 and SUDHL-4 cells, and control cells were treated with equal amounts of PBS. The proliferation, migration, apoptosis and reactive oxygen (ROS) were detected by CCK8, transwell, flow cytometry (FC) and Multifunctional Fluorescence Enzyme Marker, respectively in vitro. The engraftment, tumor growth, dissemination and survival time were observed in BALB/c nude mice and NOD-SCID mice. Results: Iron oxide nanoparticles inhibited DLBCL cells proliferation, migration and anti-apoptosis ability. The mechanism involved in the proliferation and migration of DLBCL cells by promoting the production of ROS. Furthermore, administration of iron oxide nanoparticles decreased tumor growth and dissemination of DLBCL cells, and increased survival time in the xenograft model. Summary/Conclusion: Our study demonstrates that iron oxide nanoparticles cound inhibit DLBCL cells proliferation, migration, and promote apoptosis. The supplement of iron may, therefore, be a potential target for anticancer therapy in DLBCL.
PB1770: REASONS FOR CHANGES OF BONE FORMATION PROCESSES IN CHILDREN WITH ALL LIVING IN RADIOACTIVELY CONTAMINATED TERRITORIES OF UKRAINE
Authors: K. Bruslova, N. Tsvietkova, L. Lyashenko, T. Pushkareva, I. Tryhlib, L. Honchar, S. Iatsemyrskyi
Journal: HemaSphere (2022)

Background: The state of bone structures, stromal microenvironment of the bone marrow and their hormonal regulation can be affected by iron metabolism. The mechanisms of increased bone density (IBD) in children with ALL deserve special attention. Aims: Identify the reasons of elevated bone density in children with ALL, who living in radiatioactively contaminated areas (RCA). Methods: 96 children aged 2 to 18 years with common-B ALL were examined after completion of maintenance therapy according to the protocol. The children lived at the RCA of Ukraine and were examined from 2012 to 2021. Data were studied in a comparative aspect in ALL children of 2 groups: Group I (n = 36) - with elevated IBD, above 100 units (117.4 ± 10.2 units), Group II (n = 60) - with standard IBD (100-85 units, 87.4 ± 9.1 units). Bone fractures in the anamnesis, dental caries, obesity, biochemical parameters of blood (amino acids in urine, serum ferritin (SF), serum alkaline phosphatase (AF), cholesterol, calcium, vitamin D, free thyroxine, thyroid-stimulating hormone, pituitary hormone, cortisol) as IBD were evaluated. The doses of bone marrow irradiation in patients according to their length of stay on RCA were calculated. Conducted statistical processing of materials (t-Student, Spearman’s correlation coefficient, U-Test). Results: The distribution of children by age in both groups did not differ. Boys (52 out of 60) predominated in Group I and in 30% of patients the levels of SF exceeded 500 ng / ml (728.8 ± 12.3 units). In children of both groups, a direct correlation was found between IBD and SF (p <0.001 and p <0.01, respectively). In children of Group I there was a direct relationship between IBD and fractures frequency (p <0,01). There were more children with low levels of total serum protein and glycine (p <0.01) in Group I, as number of children with high levels of alkaline phosphatase and cholesterol were less (p <0.05). IBD was inversely correlated with cortisol levels (rs = -0.73; p <0.001) and alkaline phosphatase activity (rs = -0.21; p <0.05). Dental caries in children in Group I was less frequent than in Group II (p <0.05). Survival of children was directly correlated with IBD (p <0.001). Irradiation doses in patients of Groups I and II ranged from 0.03 to 5.51 mSv (average 4.01 ± 0.17 mSv and 3.66 ± 0.18 mSv, respectively). In children, regardless of the surveillance group, there was a direct correlation between radiation dose, age of the child and the presence of obesity (p <0.001). Summary/Conclusion: The state of bone homeostasis in children with ALL depends on anabolic and catabolic metabolic processes that provide energy substrate for bone formation, the level of iron stores in the body and hormonal regulation.
P880: OVEREXPRESSION OF PFKFB4 PROMOTES ADAPTATION TO HYPOXIC MICROENVIRONMENT IN MULTIPLE MYELOMA
Authors: J. Yang, F. Wang, B. Chen
Journal: HemaSphere (2022)

Background: Multiple myeloma (MM) is a hematological malignancy with monoclonal proliferation of plasma cells, which is closely related to hypoxic bone marrow microenvironment. Previous studies have found that 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is involved in glycolysis, cell cycle progression, autophagy, and metastasis in various tumor diseases and overexpression of PFKFB4 is associated with poor prognosis. However, the underlying mechanism of PFKFB4 in hypoxia adaptation in MM has not been reported. Aims: The aim of this study was to explore the role of PFKFB4 in MM cells adaptation to the hypoxic BM microenvironment and provide potential therapeutic target for clinical treatment. Methods: We analyzed expression profile GSE80140 and GSE80545 downloaded from National Center for Biotechnology Information-Gene Expression Omnibus (NCBI-GEO) database, and conducted cell transcriptome sequencing. 5MPN, a specific inhibitor of PFKFB4, was employed to evaluate the effect of PFKFB4 in hypoxia adaptation in MM by cell proliferation, apoptosis, and cycle assays, F-2,6-BP measurement, and Western blot. Results: MM cell lines (RPMI-8226 and U266) was found to express higher level of PFKFB4 under hypoxia (1% O2) compared to normoxia (20% O2). 5MPN inhibited MM cells proliferation, suppressed intracellular F-2,6-BP concentration, and induced cell cycle arrest in G1 phase. Inhibition of PFKFB4 function had no significant effect on inducing cell apoptosis. Western blot detected the expression of proliferation, apoptosis and cell cycle related proteins, and the results were consistent. Summary/Conclusion: Overexpression of PFKFB4 promotes MM proliferation and cell cycle progression. 5MPN effectively reserves the process, suggesting that PFKFB4 is a potential therapeutic target in MM.
Treatment Represents a Key Driver of Metastatic Cancer Evolution
Authors: Ditte S. Christensen, Johanne Ahrenfeldt, Mateo Sokač, Judit Kisistók, Martin K. Thomsen, Lasse Maretty, Nicholas McGranahan, Nicolai J. Birkbak
Journal: Cancer Research (2022)

Metastasis is the main cause of cancer death, yet the evolutionary processes behind it remain largely unknown. Here, through analysis of large panel-based genomic datasets from the AACR Genomics Evidence Neoplasia Information Exchange project, including 40,979 primary and metastatic tumors across 25 distinct cancer types, we explore how the evolutionary pressure of cancer metastasis shapes the selection of genomic drivers of cancer. The most commonly affected genes were TP53, MYC, and CDKN2A, with no specific pattern associated with metastatic disease. This suggests that, on a driver mutation level, the selective pressure operating in primary and metastatic tumors is similar. The most highly enriched individual driver mutations in metastatic tumors were mutations known to drive resistance to hormone therapies in breast and prostate cancer (ESR1 and AR), anti-EGFR therapy in non-small cell lung cancer (EGFR T790M), and imatinib in gastrointestinal cancer (KIT V654A). Specific mutational signatures were also associated with treatment in three cancer types, supporting clonal selection following anticancer therapy. Overall, this implies that initial acquisition of driver mutations is predominantly shaped by the tissue of origin, where specific mutations define the developing primary tumor and drive growth, immune escape, and tolerance to chromosomal instability. However, acquisition of driver mutations that contribute to metastatic disease is less specific, with the main genomic drivers of metastatic cancer evolution associating with resistance to therapy.This study leverages large datasets to investigate the evolutionary landscape of established cancer genes to shed new light upon the mystery of cancer dissemination and expand the understanding of metastatic cancer biology.
Implementation of a controlled human infection model for evaluation of HCV vaccine candidates
Authors: Eleanor Barnes, Graham S. Cooke, Georg M. Lauer, Raymond T. Chung
Journal: Hepatology (2022)

Hepatitis C virus (HCV) remains a major global health concern. Directly acting antiviral (DAA) drugs have transformed the treatment of HCV. However, it has become clear that, without an effective HCV vaccine, it will not be possible to meet the World Health Organization targets of HCV viral elimination. Promising new vaccine technologies that generate high magnitude antiviral T and B cell immune responses and significant new funding have recently become available, stimulating the HCV vaccine pipeline. In the absence of an immune competent animal model for HCV, the major block in evaluating new HCV vaccine candidates will be the assessment of vaccine efficacy in humans. The development of a controlled human infection model (CHIM) for HCV could overcome this block, enabling the head‐to‐head assessment of vaccine candidates. The availability of highly effective DAA means that a CHIM for HCV is possible for the first time. In this review, we highlight the challenges and issues with currently available strategies to assess HCV vaccine efficacy including HCV “at‐risk” cohorts and animal models. We describe the development of CHIM in other infections that are increasingly utilized by trialists and explore the ethical and safety concerns specific for an HCV CHIM. Finally, we propose an HCV CHIM study design including the selection of volunteers, the development of an infectious inoculum, the evaluation of host immune and viral parameters, and the definition of study end points for use in an HCV CHIM. Importantly, the study design (including number of volunteers required, cost, duration of study, and risk to volunteers) varies significantly depending on the proposed mechanism of action (sterilizing/rapid viral clearance vs. delayed viral clearance) of the vaccine under evaluation. We conclude that an HCV CHIM is now realistic, that safety and ethical concerns can be addressed with the right study design, and that, without an HCV CHIM, it is difficult to envisage how the development of an HCV vaccine will be possible.
PB2198: EFFECTS OF NOVEL CORONAVIRUS VACCINATION ON THE COLLECTION OF PERIPHERAL BLOOD HEMATOPOIETIC STEM CELLS FROM HEALTHY DONORS
Authors: Z. Wang, S. Cui, J. Xu, X. Tan, Y. Tian, X. Tang, Y. Wang
Journal: HemaSphere (2022)

Background: With the development and marketing of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccine, vaccination has become an effective way to block the novel coronavirus disease 2019 (COVID-19) the most efficient way to spread. Hematopoietic stem cell transplantation (HSCT) is one of the important means for the treatment of aplastic anemia, multiple myeloma, leukemia, lymphoma, myelodysplastic syndrome, autoimmune diseases and other hematological diseases. Peripheral blood hematopoietic stem cell (PBSC) transplantation has the advantages of convenient collection, small impact on donors, good tolerance of donors and recipients, fast and durable recovery of hematopoietic function and immune function of patients after transplantation, and low transplantation-related mortality. However, it is unknown whether the novel coronavirus vaccine has any effect on the collection of peripheral blood hematopoietic stem cells from transplant donors. Aims: To compare the effects of unvaccinated and vaccinated novel coronavirus vaccine on the collection of peripheral blood hematopoietic stem cells from healthy donors. Methods: A retrospective analysis was made on the 112 times of peripheral blood hematopoietic stem cell apheresis conducted by 59 healthy donors who were not vaccinated with the new crown vaccine and 41 healthy donors who were vaccinated with the new crown vaccine in the Affiliated Hospital of Shandong University of traditional Chinese medicine from February 6, 2017 to February 11, 2022, and the quality of hematopoietic stem cell collection products was evaluated by MNC count and CD34+ count. Results: There was no significant difference in gender, age and collection times between the two groups (P>0.05). The MNC count collected in the unvaccinated group was (7.99±2.38) ×108/kg, and the CD34+ count was (3.24±0.69) ×106/kg. The MNC count collected in the vaccinated group was (7.97±3.71)×108/kg, and the CD34+ count was (3.41±0.59) ×106/kg. There was no significant difference between the two groups (P>0.05). - Unvaccinated group Vaccination group P Sex 0.441 Male 39 (66.10%) 24 (58.54%) Female 20 (33.90%) 17 (41.46%) Collection times Once 52（88.14%） 36（87.80%） 0.960 Twice 7（11.86%） 5（12.20%） Age 35.47±14.93 31.54±14.36 0.191 MNC 7.99±2.38 7.97±3.71 0.980 CD34+ 3.24±0.69 3.41±0.59 0.194 Summary/Conclusion: In this preliminary study, we found that the novel coronavirus vaccine had no effect on MNC and CD34+ counts in peripheral blood hematopoietic stem cell collection products from healthy donors. However, these findings require further investigation in larger randomized studies to be validated.
BCG hydrogel promotes CTSS-mediated antigen processing and presentation, thereby suppressing metastasis and prolonging survival in melanoma
Authors: Mirela Kremenovic, Alfred A Chan, Bing Feng, Lukas Bäriswyl, Steve Robatel, Thomas Gruber, Li Tang, Delphine J Lee, Mirjam Schenk
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The use of intralesional Mycobacterium bovis BCG (intralesional live BCG) for the treatment of metastatic melanoma resulted in regression of directly injected, and occasionally of distal lesions. However, intralesional-BCG is less effective in patients with visceral metastases and did not significantly improve overall survival. Methods We generated a novel BCG lysate and developed it into a thermosensitive PLGA-PEG-PLGA hydrogel (BCG hydrogel), which was injected adjacent to the tumor to assess its antitumor effect in syngeneic tumor models (B16F10, MC38). The effect of BCG hydrogel treatment on contralateral tumors, lung metastases, and survival was assessed to evaluate systemic long-term efficacy. Gene expression profiles of tumor-infiltrating immune cells and of tumor-draining lymph nodes from BCG hydrogel-treated mice were analyzed by single-cell RNA sequencing (scRNA-seq) and CD8 + T cell receptor (TCR) repertoire diversity was assessed by TCR-sequencing. To confirm the mechanistic findings, RNA-seq data of biopsies obtained from in-transit cutaneous metastases of patients with melanoma who had received intralesional-BCG therapy were analyzed. Results Here, we show that BCG lysate exhibits enhanced antitumor efficacy compared to live mycobacteria and promotes a proinflammatory tumor microenvironment and M1 macrophage (MΦ) polarization in vivo. The underlying mechanisms of BCG lysate-mediated tumor immunity are dependent on MΦ and dendritic cells (DCs). BCG hydrogel treatment induced systemic immunity in melanoma-bearing mice with suppression of lung metastases and improved survival. Furthermore, BCG hydrogel promoted cathepsin S (CTSS) activity in MΦ and DCs, resulting in enhanced antigen processing and presentation of tumor-associated antigens. Finally, BCG hydrogel treatment was associated with increased frequencies of melanoma-reactive CD8 + T cells. In human patients with melanoma, intralesional-BCG treatment was associated with enhanced M1 MΦ, mature DC, antigen processing and presentation, as well as with increased CTSS expression which positively correlated with patient survival. Conclusions These findings provide mechanistic insights as well as rationale for the clinical translation of BCG hydrogel as cancer immunotherapy to overcome the current limitations of immunotherapies for the treatment of patients with melanoma.
Nivolumab in patients with relapsed or refractory peripheral T-cell lymphoma: modest activity and cases of hyperprogression
Authors: N Nora Bennani, Hyo Jin Kim, Levi D Pederson, Pamela J Atherton, Ivana N Micallef, Gita Thanarajasingam, Grzegorz S Nowakowski, Thomas Witzig, Andrew L Feldman, Stephen M Ansell
Journal: Journal for ImmunoTherapy of Cancer (2022)

Peripheral T-cell lymphomas (PTCL), a heterogeneous group of mature aggressive non-Hodgkin's lymphomas, carry a worse prognosis for most subtypes when compared with their B-cell counterparts. Despite recent approval of newer therapies, the outlook for patients with relapsed/refractory (RR) PTCL remains poor and new treatment strategies are clearly needed. Targeting the profoundly immunosuppressive tumor microenvironment in PTCL is one such approach. To determine whether immune checkpoint blockade targeting program death receptor 1 would be effective in PTCL, we conducted an investigator-initiated phase 2 prospective study of single-agent nivolumab for RR PTCL. We report here results of the pre-specified interim analysis.The primary objective was to assess the overall response rate (ORR). Secondary objectives were to assess safety and tolerability of nivolumab in PTCL and to assess progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Hyperprogressive disease (HPD) was defined as time-to-treatment failure of less than or equal to one month from initiation of therapy.Twelve patients who received at least one cycle of nivolumab were included in this interim analysis. Half (6/12) of the patients had angioimmunoblastic T-cell lymphoma (AITL), 3/12 had PTCL, not otherwise specified. Most (11/12) were advanced stage, had extranodal disease (97.1%) and had received a prior autologous stem cell transplant (50%). The ORR was 33% (95% CI: 12.3 to 63.7%) with two complete response and two partial response. The median PFS was however short at 2.7 months (95% CI: 1.5 to NE); and the median OS was 6.7 months (95% CI: 3.4 to NE). The median DOR was also short at 3.6 months (95% CI: 1.9 to NE). HPD occurred in four patients, three of whom had AITL. Observed grade 3 and higher adverse events (AEs) were non-hematologic in 5/12 (42%), while hematologic AEs were seen in 3/12 (25%).Nivolumab had modest clinical activity in R/R PTCL. Due to a high number of hyperprogression and short DOR, a decision was made to halt the study. These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases.NCT03075553.